Question of the Week

For June 7, 2016

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Hereditary neutrophiliaBronchiectasisChronic neutrophilic leukemiaChronic use of inhaled budesonideCigarette smoking

Key Learning Point View Case Presentation

The most typical cause of long-standing mild leukocytosis and neutrophilia in a patient with asthma who smokes cigarettes is cigarette smoking.

Detailed Feedback

Cigarette smoking is a common cause of mild leukocytosis, and the more packs of cigarettes smoked per day, the greater the elevation in the absolute neutrophil count. Normalization of the leukocyte count may occur after as little as one year to as long as several years after the cessation of smoking, but may take up to five years. Inflammation related to smoking has been invoked as a cause of neutrophilic leukocytosis, but the exact mechanism is unknown.

Chronic neutrophilic leukemia is associated with neutrophilia and splenomegaly and with blood counts that are likely to worsen over time.

Hereditary neutrophilia is an extremely rare disorder caused by an autosomal mutation in the CSF3R gene, which results in a constitutively active granulocyte colony-stimulating factor receptor. This condition manifests with neutrophilia and splenomegaly.

The patient's stable clinical course suggests that an undiagnosed chronic infection, which can be associated with bronchiectasis, is unlikely.

Inhaled glucocorticoids reduce airway neutrophilia. Systemic high-dose glucocorticoid use can be associated with a mild neutrophilia (average increase in absolute neutrophil count of 4000 per mm3), but this effect is not seen with inhaled glucocorticoids because the systemically absorbed dose is insufficient to affect neutrophil levels.

Last reviewed Jan 2019. Last modified Jan 2019.


Riley LK and Rupert J. Evaluation of patients with leukocytosis. Am Fam Physician 2015 Dec 1; 92:1004.   > View Abstract

Parry H et al. Smoking, alcohol consumption, and leukocyte counts. Am J Clin Pathol 1997 Jan; 107:64.   > View Abstract

Schwartz J and Weiss ST. Cigarette smoking and peripheral blood leukocyte differentials. Ann Epidemiol 1994 May; 4:236.   > View Abstract


  1. Christian Sperling June 7, 2016 at 11:31 am - Reply  >

    The discussion of budenoside side effects I find somehow contradictory: when leucytosis occurs (quite infrequent) it is indeed caused by an increase of neutrophils (= neutrophilia). I agree that smoking is the likely cause in this case.

    • Sheldon Ball June 7, 2016 at 12:30 pm - Reply  >

      I would have liked to see additional evidence base to substantiate the claim regarding budesonide.

    • Afisulahi Maiyegun June 7, 2016 at 2:36 pm - Reply  >

      Leucocytosis could also be due to lymphocytosis.

  2. Sujit Bhattacharya June 7, 2016 at 11:39 am - Reply  >

    These well thought case histories are very educative. I like them.

  3. B Chacko June 7, 2016 at 11:52 am - Reply  >

    One reference quoted had mean white count of 5.56 among non-smokers and 6.76 in heavy smokers. Another showed a 27% increase in white count among smokers. Change in neutrophil counts are more modest. NHANES data was gathered among adults aged 30 to 75 years.
    A 29 year old asthmatic with WBC 14, neutrophilia and 4d of new symptoms suggests the need to watch closely for deterioration rather than reassurance. The intended teaching point is not supported by the case or relevant references. The idea of smoking induced leukocytosis was put forth in the Lancet by Howell in 1970.

    • de Clari June 9, 2016 at 5:28 am - Reply  >

      The patient has dyspnea, wheezing and slightly decreased saturation , which are not correlated to smokers neutrophilia.Smoking does not necessarily cause dyspnea and wheezing although it can cause desaturation owing to an increase in methemoglobin (induced by oxydants in smoke) which is unable to carry oxygen.This patient probably has an exacerbation of his chronic smokers bronchitis, due to a viral infection.

      • Franz Josef Abis June 9, 2016 at 5:39 am - Reply  >

        Exacerbations of asthma can be caused by intercurrent viral RTIs ,prevalently owing to inflammation of the bronchial mucosa even in the abscence of chronic smoker’s bronchitis

        • Sigfrid von Juvalt June 10, 2016 at 11:45 am - Reply  >

          Furthermore, dear Dr Abis, smoking asthma patients loose the response to costicosteroids because oxidants in cigarette smoke reduce the pool of histone deacetylases : the chromatin cannot be opened to allow corticoids to combine with their corticoid response element, and initiate transscription of antiinflammatory proteins. (see Ito & Barnes, NEJM 2005). In this case I think like many other commentators, that this patient has more than smoke-related leukocytosis, namely acute (viral) bronchitis, or viral exacerbation of chronic bronchitis.

      • Dr Anwar June 10, 2016 at 1:34 pm - Reply  >

        Dear in viral infection there would lymphocytosis. It could be bacterial bronchitis which led to exacerbation of bronchial asthma

  4. eman June 7, 2016 at 12:12 pm - Reply  >


  5. Stefan Rauh June 7, 2016 at 12:28 pm - Reply  >

    i highly appreciate the question’s intent and learning point (and answered tobacco use) … Just a word of caution, since i am regularly confronted with patients trying to establish a “linear” relationship between two or more blood samples within long observation intervals: they obviously do not have to be in relation (but can also signify recurrent events /infections ) . To my mind, the leucocytosis here observed could in the context of the described symptoms in this case also be due to superinfection (bronchitis will not be seen on x-ray , and basal pneumonia missed)… i would have required more information as cropper pro calcitonin , and would have suggested close follow-up in every day practice

  6. Conor McCartney June 7, 2016 at 1:19 pm - Reply  >

    I learned something this week. Definitely appreciated this case! Thanks.

  7. Dr Paulsen June 7, 2016 at 1:25 pm - Reply  >

    Moderately elevated leuko-counts in smokers are common, one wonders what this patient’s underlying problem might be, 93% oxygen saturation I find quite low…

    • Dr. Lyn June 9, 2016 at 1:47 am - Reply  >

      Agree a-a gradient likley to be elevated with that 93%

  8. Dr. Josh June 7, 2016 at 2:03 pm - Reply  >


  9. Ruwan June 7, 2016 at 2:37 pm - Reply  >

    Good question.thanks.

  10. arezoo June 7, 2016 at 3:23 pm - Reply  >

    Very interesting. good to know

  11. Dr Simpson June 7, 2016 at 6:11 pm - Reply  >

    Whilst I agree with smoking being the likely aetiology, the statement that inhaled glucocorticoids not inducing neutrophilia is incorrect. Its well established that systemic absorption glucocorticoids may result in a chronic low grade neutrophilia.

  12. Debabrata Das June 7, 2016 at 6:59 pm - Reply  >

    There was tachypnea in this patient and no obvious infection. Is there something other than smoking contributing to high count like obesity. We know association of Asthma and overweight state leading to mild tachypnea and high RBC, WBC & Platelet counts.

  13. Siraj Siddiqui June 7, 2016 at 7:25 pm - Reply  >

    Good learning cases

  14. Konstantin June 7, 2016 at 7:30 pm - Reply  >

    I am interested in the clinical picture of the patient’s condition worsening . Worsening of asthma has come for 4 days . Decreased oxygen saturation and dyspnea appeared . That is, there are signs of deterioration of asthma . Asthma is frequently deteriorates under the influence of different factors that can cause infection think about despite normal at elevated temperature neutropenia . Although , in terms of the causes of leukocytosis and neytrofilleza in patients with asthma – an interesting question and the answer .

  15. Konstantin June 7, 2016 at 7:33 pm - Reply  >

    at elevated temperature neutropenia…….(neytrofillia).Sorry, typo.

  16. Domingo Campusano June 7, 2016 at 11:18 pm - Reply  >

    I Want to remember that the cigarete smoking don’t cause only leukocytosis and neutrofilia,more fricuent cause polyglobulia,

  17. Mohit June 8, 2016 at 2:01 am - Reply  >

    Also notable is recent acute worsening with dyspnoea and expiratory wheeze… Not explained fully.. Point due noted although…!

  18. Santoso Adhiwana June 8, 2016 at 2:39 am - Reply  >

    Thanks for the informative case-presentation. Anyway, keeping in mind of the patient’s chronic disease, it is worth to follow-up the development of bronchiectasis.

  19. Ahmed hawash June 8, 2016 at 3:55 am - Reply  >

    I like more cases like this

  20. K K Pandita June 8, 2016 at 9:41 am - Reply  >

    I Liked it. This is the 1st time I learnt that cigarette smoking causes mild neuttophilic leukocytosis. Thanks NEJM.

  21. Lorenzo June 8, 2016 at 9:47 am - Reply  >

    Then what’s the cause of dyspnea in this man?. Sudden airways inflammation in a long standing smoker?

    • Jeanne Kropko June 10, 2016 at 8:14 pm - Reply  >

      It was a sudden change, a low saturation and the difficulty brought him to the doctor’s office it is hard to accept that the change is caused by a chronic condition

  22. Lorenzo June 8, 2016 at 9:48 am - Reply  >

    Then what’s the cause of dyspnea. Sudden intolerance to smoking?

  23. Alejandro Quiñonez June 8, 2016 at 11:27 am - Reply  >

    Again… the Cigarette smoking
    But remember… in developing countries, cooking with wood fire since the childhood is about the same risk…

  24. Rizwan Rauf June 8, 2016 at 5:43 pm - Reply  >

    Though smoking does causes leucocytosis, but here,this leucocytosis seems to be steroid induced.
    Endogenous steroid release from stress or treatment with exogenous corticosteroids results in a leukogram with multiple changes.
    Lymphopenia is the most consistent change, same for eosinopenia, and mature neutrophilia is usually present,
    Neutrophilia is due to decreased adherence to the vascular endothelium, which inhibits margination and increases circulating time.

    There may also be increased marrow release of neutrophils.

    Lymphocytes become redistributed to lymphoid tissues instead of remaining in circulation.
    This response may be misinterpreted as inflammation, but a left shift is not usually present.

  25. husam salim abbas June 9, 2016 at 1:43 pm - Reply  >

    To what degree smoking cause leukocytosis…..

  26. elias azar,M.D,M.P.H.,A.F.I.M June 9, 2016 at 8:12 pm - Reply  >

    Super nice case

    I thought it is due to budesonide!!!!!!!!!!!!!!!!!!!!!1

    Thank u for knowing better!!!!!!!!!!!!!!!!!

  27. Mary Lou Ashur June 11, 2016 at 9:20 am - Reply  >

    Okay, point taken, smoking causes neutrophilia .
    There are many potential teaching points for the case of a man with asthma exacerbation who is smoking.
    Cigarette smoking in an asthmatic is obviously BAD. Smoking cessation is as critical for the doctor to discuss as is writing Rx for beta agonists and inhaled steroids
    Let’s discuss other aspects of asthma that could be on board exams or in our own patients:
    1) detecting an asthma exacerbation can be a challenge, as some pts are sensitive to changes while others are not; I ask patients use peak expiratory flow meters, get baseline measurements when they are healthy. They check from time to time, as well as when they feel their asthma control is failing. 20% change from baseline is concerning; 50% decrease is a sever attack.
    2)Have patients tune into and report their own symptoms, such as fatigue with exercise, cough, tight chest, dyspnea, and of course wheezing.
    3) Otherwise healthy patients still die every year of asthma; be aware of risk factors for severe asthma:
    At highest risk for severe asthma exacerbations I made up the mneumonic: CHIASM
    C CHF or heart disease
    H Hospitalizations ICU visits, and multiple ER visits in the last year.
    I Intubation history
    A Abuse/ Altered mental state – poor perception of breathing status from drug abuse or mental illness
    S Smoking;
    M Medications – steroid taper, poor compliance with inhaled steroids.

    Thank you.

  28. Enrico Motz June 12, 2016 at 8:33 am - Reply  >

    Smoking can not cause by itself this man’s neutrophilia, it can favour stasis and infection, preferably bacterial. Also, inhalatory corticosteroids are an unlikely cause of neutrophilia. I would recommend suspension of smoking and a course of broad-spectrum antibiotics

  29. missana June 14, 2016 at 12:36 am - Reply  >

    Thank you for this learning presentation.
    Before i had no idea whether smoking and steroids can cause neutrophilia. This reminds me of a patient with COPD who had elevated neutrophils even after a course of broad spectrum antibiotics. Thank you very much

  30. ARNAB BANERJEE June 22, 2016 at 4:27 am - Reply  >

    this is extremely beautuful idea from nejm regarding this clinical would be bettr if uploaded as QUESTION OF THE DAY..i mean a new this type question everyday rather weekly..

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